Chiral Acylation with N-(Protected α-Aminoacyl)benzotriazoles for Advantageous Syntheses of Peptides and Peptide Conjugates

Abstract

N-(Protected a-aminoacyl)benzotriazoles are efficient intermediates for N-and O-aminoacylation. These intermediates enable fast preparations of biologically relevant peptides and peptide conjugates in high yields and purity, under mild reaction conditions, with full retention of the original chirality. The developed methodology allows simple solution-and solid-phase preparative techniques to generate complex peptides and peptide conjugates and serves as a platform for generating diverse medicinal chemistry building block libraries involving amino acid and heterocyclic moieties crucial for drug development.

Syntheses of Hydrazino Peptides and Conjugates

“…The coupling reaction between α-hydrazino acids 8a-8d and Cbz-protected α-aminoacylbenzotriazoles 10a-10f [30] under microwave irradiation (70°C and 65 W) for 15 min afforded new hydrazino hybrid dipeptides 11a-11f (42-71 %). Comparatively low yields were obtained in case of compounds 11b and 11c as a result of purifying these compounds by column chromatography, but no side products were obtained after this step except for some unreacted starting material (see Schemes 3 and 4 and Table 3).…”

Syntheses of Chiral N‐(Protected) Tri‐ and Tetrapeptide Conjugates

“…Previously, we reported the facile synthesis of amino acid conjugates with steroids, terpenes, and sugars. (32) Herein, we present the extension of our methodology for the convenient and efficient formation of Cbz‐protected tri‐ and tetrapeptide conjugates with sugars, steroids, terpenes, and heterocyclic nuclei of biological importance.…”

S‐ to N‐Acyl transfer in S‐acylcysteine isopeptides via 9‐, 10‐, 12‐, and 13‐membered cyclic transition states

“…We prepared starting monoisotripeptide 7 for study of S → N ‐acyl migration via 9‐membered cyclic transition state as illustrated in Scheme . Boc‐protected β‐alanine 1 was converted into the corresponding benzotriazolide 2 by the standard method . l ‐Cysteine was reacted with the Boc‐β‐alanine benzotriazolide 2 in aqueous acetonitrile (MeCN/H 2 O, 7/3) containing 1 equiv of Et 3 N for 1 h at 20 °C to give the Boc‐β‐alanyl‐cysteine dipeptide 4 (68%).…”